Journal
INTERNATIONAL JOURNAL OF ONCOLOGY
Volume 50, Issue 3, Pages 964-974Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/ijo.2017.3861
Keywords
malignant glioma; hypoxia; p53; autophagy; autophagic; apoptosis
Categories
Funding
- Chi-Mei Medical Center [102CM-TMU-14-1]
- Wan-Fang Hospital [105-swf-04]
- Health and Welfare Surcharge of Tobacco Products, Taiwan [MOHW105-TDU-B-212-134001]
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Malignant glioma is the most aggressive brain tumor. Hypoxic condition has been explored for killing cancer stem cells or drug-resistant tumor cells. This study investigated the effects of hypoxia on autophagic death and the possible mechanisms. Exposure of human malignant glioma U87-MG cells to cobalt chloride (CoCl2) increased cellular hypoxia-inducible factor-l alpha levels and concurrently decreased cell viability concentration- and time-dependently. In parallel, treatment with CoC1(2), suppressed proliferation of human U87-MG cells. Autophagic cells and levels of LC3-II were concentration- and time-dependently induced in human U87-MG cells after exposure to CoC1(2),. However, pretreatment with 3-mehyladenine (3-MA) and chloroquine, inhibitors of cell autophagy, caused significant alleviations in CoC1(2),induced cell autophagy. In contrast, exposure to rapamycin, an inducer of cell autophagy, synergistically induced hypoxiainduced autophagy of U87-MG cells. Administration of human U87-MG cells with CoC1(2), triggered caspase-3 activation and cell apoptosis. Interestingly, pretreatment with 3-MA and chloroquine remarkably suppressed CoC1(2)-induced caspase-3 activation and cell apoptosis. Application of p53 small interference (si)RNA into human U87-MG cells downregulated levels of this protein and simultaneously lowered hypoxiaand 3-MA-induced alterations in cell autophagy, apoptosis, and death. The hypoxia-induced autophagy and apoptosis of DBTRG-05MG cells were significantly lowered by 3-MA pretreatment and p53 knockdown. Therefore, the present study shows that CoC1(2) treatment can induce autophagy of human glioma cells and subsequent autophagic apoptosis via a p53-dependent pathway. Hypoxia-induced autophagic apoptosis may be applied as a therapeutic strategy for treatment of glioma patients.
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